International Journal of Molecular Sciences Review The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight against Cancer Ahmed Elkamhawy 1,2 , Qili Lu 1, Hossam Nada 1 , Jiyu Woo 1, Guofeng Quan 1 and Kyeong Lee 1,* 1 College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; [email protected] or [email protected] (A.E.); [email protected] (Q.L.); [email protected] (H.N.); [email protected] (J.W.); [email protected] (G.Q.) 2 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt * Correspondence: [email protected] Abstract: Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity. Citation: Elkamhawy, A.; Lu, Q.; Keywords: discoidin domain receptor (DDR); cancer; kinase inhibitors; structure-activity relation- Nada, H.; Woo, J.; Quan, G.; Lee, K. ship (SAR); DDR1 and DDR2 The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight against Cancer. Int. J. Mol. Sci. 2021, 22, 6535. https://doi.org/ 1. Introduction 10.3390/ijms22126535 Discoidin domain receptor (DDR), discovered in the early 1990s, belongs to a family of the transmembrane receptor tyrosine kinases (RTKs) which acts as a hub for signal Academic Editor: Stanislav Kalinin transduction initiation. A discoidin motif (DS) which encompasses the collagen-binding site is a specific structural feature that distinguishes the human DDRs (DDR1 (CD167a) Received: 21 May 2021 and DDR2 (CD167b)) from other RTKs. While DDR1 has five isoforms (DDR1a, DDR1b, Accepted: 13 June 2021 DDR1c, DDR1d, and DDR1e) different in the extent of glycosylation, protein interactions, Published: 18 June 2021 expression patterns, phosphorylation, as well as functions, DDR2 has only a single isoform to date. DDR1a, b, and c are found to be kinase-active, while DDR1d and e are kinase Publisher’s Note: MDPI stays neutral domain-deficient receptors with unknown function. It is well-established that ligands with regard to jurisdictional claims in published maps and institutional affil- of typical RTKs are peptide-like growth factors, on the other hand, DDR activation is iations. controlled by numerous types of triple-helical collagens. DDR1 is mainly expressed in epithelial cells of different tissues while DDR2 is found in mesenchymal cells including fibroblasts, myofibroblasts, smooth muscle cells, and chondrocytes. DDR plays a key role in the production and degradation processes of collagen and the essential cellular processes such as proliferation, differentiation, adhesion, in addition to matrix remodeling [1–3]. Copyright: © 2021 by the authors. Collective evidence suggests that dysregulation of DDR is attributed to different Licensee MDPI, Basel, Switzerland. human disorders, such as cancer, fibrosis, atherosclerosis, neurodegeneration, and other in- This article is an open access article flammatory disorders. Accordingly, DDR has been considered as novel potential molecular distributed under the terms and conditions of the Creative Commons target, mainly for drug development of cancer. Many DDR inhibitors have been disclosed Attribution (CC BY) license (https:// highlighting the promising potential of DDR inhibition as a novel therapeutic strategy [4,5]. creativecommons.org/licenses/by/ From a medicinal chemistry perspective, this review offers an updated overview on the 4.0/). Int. J. Mol. Sci. 2021, 22, 6535. https://doi.org/10.3390/ijms22126535 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 6535 2 of 27 development journey of the most promising DDR small molecule inhibitors including design, structure-activity relationship (SAR), biological activity, and selectivity. 2. Structure and Activation of DDR Kinase Similar to the classic RTKs, which share high structural features, the molecular struc- ture of DDR consists of three main domains: an extracellular binding one, a transmembrane domain (TM), and an intracellular domain (Figure1). In the extracellular part of DDR, there are two main components: a unique DS motif and a DS-like domain responsible for the collagen binding. The TM domain consists of an extracellular juxtamembrane (JM) region possessing phosphorylatable tyrosine amino acids (the docking site for DDR binding proteins), and a TM helix which arbitrates collagen independent receptor dimerization. The intracellular domain contains an intracellular JM region and a catalytic tyrosine kinase do- main which controls the intrinsic enzymatic activity [6]. The kinase domains of DDR1 and DDR2 were discovered to have a high degree of sequence and morphological homology with those of Abl and c-Kit kinases [7]. Glycine-rich loop, A-loop, DFG motif, and C-helix are among the loops or motifs found in the DDR1 kinase domain, which are also found in other RTKs [8]. However, DDR1 and DDR2 are activated by different forms of collagen rather than soluble growth factors, unlike other RTKs [9]. Collagen binding activates the tyrosine kinase Src to phosphorylate tyrosines in the DDR activation loop. Accordingly, the activation of kinase domain in DDR autophosphorylates numerous additional tyrosines in the JM region, which subsequently leads to the recruitment of downstream adaptor pro- teins to regulate cell behavior. In comparison to ligand-induced dimerization in other RTKs, intrinsic DDR dimerization occurs without recognizing the ligand [10]. Furthermore, while typical RTK activation is triggered in just a few seconds after binding to a ligand, DDR phosphorylation is noticeably slow; several hours are needed to get full activation [9,11]. An additional insulin-like growth factor (IIGF) system-based activation model of DDR was recently discovered. In a collagen-independent manner, insulin, IGF1, and IGF2 were found to upregulate DDR1 expression and phosphorylation [3,12]. Figure 1. Structures and subtypes of DDR1 and DDR2. Reprinted from with permission Ref. [13]. Int. J. Mol. Sci. 2021, 22, 6535 3 of 27 3. Biological Role of DDR Both DDR1 and DDR2 are essential regulatory factors for organ development and physiological function [9,14–18]. In addition to their important roles in cell proliferation and differentiation, DDRs were also found to have rules in cell migration, invasion, and adhesion [10,19–21]. DDR1 has an essential role in the biogenesis of multiple organs, for example, DDR1-knockout mice were found to be shorter than their littermates and to have a lactational defect in pregnant females. Multiple reproductive disorders, including infertility due to abnormal embryo implantation and abnormal mammary gland growth, were also discovered in DDR1-null mice [22,23]. In addition to extreme auditory function loss and progressive morphological changes, they displayed abnormalities in kidney and inner ear architecture [24]. DDR1 deficiency impairs adhesion and migration abilities [25]; it was reported that DDR1a is an important factor for the promotion of leukocyte migration in three-dimensional collagen lattices [20]. DDR1 mediated activated T cells were also found to bind to collagen, which enhanced T cell migration [26]. DDR2 was reported to be involved in skeletetogenesis since it was found to be important for chondrocyte proliferation [27,28]; In DDR2-null mice, skeletal disorders such as the shortening of long bones and abnormal growth of flat bones have recently been reported [29]. Another study by Kano et al., showed the critical role of DDR2 signaling in the maintenance of male spermatogenesis [30]. Skin wound-healing disorders were also observed in DDR2- knockout mice, which were primarily caused by decreased skin fibroblast proliferation and abnormal extracellular matrix remodeling [21]. Furthermore, a link has been found between DDR2 deletion or mis-sense mutation and autosomal recessive growth disorders such as Smallie (Slie) and human spondylo-meta-epiphyseal dysplasia, which is characterized by short limbs and irregular calcifications (SMED-SL) [31–35]. Overexpression of DDR2 promotes the proliferation and invasion of hepatic stellate cells mediated by matrix metalloproteinase-2 (MMP-2) [36]. It was confirmed that DDR2 is necessary for normal fibroblast spreading and migration, regardless of the presence of adhesion ligands or collagen activation [37]. Studies also suggested that DDR2 function is essential for the membrane dynamics that control the mechanical attachment of fibroblasts to the 3D collagen matrices [38]. DDR2 reduction was also found to increase the population of CD8+ T cells as well as the sensitivity to anti–programmed cell death protein 1 (PD-1) therapy [39]. 4. Role of DDR in Cancer DDR1 and DDR2 dysregulation has been linked to multiple forms of cancer. Many studies have shown that elevated